Current challenges in photoprotection

HenryW.Lim,MD,a Maria-Ivonne Arellano-Mendoza, MD,b and Fernando Stengel, MDc Detroit, Michigan; Mexico City, Mexico; and Buenos Aires, Argentina

Electromagnetic radiation in the ultraviolet, visible, and infrared ranges all produce biologic effects. Ultraviolet filters are the most well-studied photoprotective measure for the adverse effects of ultraviolet radiation. Because of the reported endocrinologic effects of oxybenzone in animal studies, its effects on coral reefs, and its photocontact allergy potential, its use has been minimized in many countries worldwide. New developments in topical antioxidants and oral and subcutaneous agents (eg, Polypodium leucotomos extract, afamelanotide, nicotinamide) with photoprotective and antiphoto- carcinogenic properties could potentially provide addition modalities for protection against the effects of visible light and infrared radiation. ( J Am Acad Dermatol 2017;76:S91-9.)

Key words: afamelanotide; antioxidant; nicotinamide; oxybenzone; photoprotection; Polypodium leucotomos extract; sunscreen.

lthough the need to prevent acute (ery- thema) and chronic (skin cancer and photo- Abbreviations used: aging) skin damage resulting from exposure 25(OH)D: 25-hydroxyvitamin D A CPD: cyclobutane pyrimidine dimer to ultraviolet (UV) radiation (UVR) (UVB and UVA) is EPP: erythropoietic protoporphyria well understood, the safest and most effective way to FDA: Food and Drug Administration achieve this still presents a number of challenges, MMP: matrix metalloproteinase ROS: reactive oxygen species specifically, in the practical implementation of sun- SPF: sun-protection factor protective measures. These include concerns about UV: ultraviolet the safety of some currently available UV filters, UVR: ultraviolet radiation whether sunscreens detrimentally affect serum vitamin-D levels, whether new nontopical agents can offer significant additional sun protection, and SUNSCREEN SAFETY AND EFFICACY how to protect against recently identified harmful Oxybenzone effects of radiation at frequencies outside the UV Oxybenzone (benzophenone-3) is an organic range of the solar spectrum. filter that absorbs both UVB and short-range UVA It should be emphasized that although sunscreen (UVA2). Because few other organic UVA filters have products are excellent means of photoprotection, been approved by the US Food and Drug they should always be part of the total photo- Administration (FDA), oxybenzone is widely used protection package, which includes seeking shade, in the United States. Concerns were expressed about wearing protective clothing and a wide-brimmed the safety of oxybenzone after reports of cases of hat, and using sunglasses. allergic and photoallergic contact dermatitis and

From the Department of Dermatology, Henry Ford Hospital, served as a consultant for La Roche-Posay, Roche, Vichy, and a Detroit ; Department of Dermatology, Hospital General de Pierre Fabre Dermo-Cosmetique/Av ene. b Mexico Dr Eduardo Liceaga ; and Fundacion del Cancer de Accepted for publication September 18, 2016. c Piel, Buenos Aires. Reprint requests: Henry W. Lim, MD, Henry Ford Medical Center, Publication of this supplement is supported by Laboratoires New Center One, 3031 W Grand Blvd, Suite 800, Detroit, MI Dermatologiques Avene. 48202. E-mail: [email protected]. Disclosure: Dr Lim has served as a consultant for Pierre Fabre Published online December 27, 2016. Dermo-Cosmetique/Avene and received research grants from 0190-9622/$36.00 Estee Lauder, Ferndale, and Allergan. Dr Arellano has served as Ó 2016 by the American Academy of Dermatology, Inc. a consultant for Galderma, Bioderma, Sanfer, Pierre Fabre http://dx.doi.org/10.1016/j.jaad.2016.09.040 Dermo-Cosmetique/Av ene, and Leo Pharma. Dr Stengel has

S91 S92 Lim, Arellano-Mendoza, and Stengel JAM ACAD DERMATOL MARCH 2017 because of its potential for endocrine disruption andIndianoceans,19 and presenting a hazard to reported in an animal model. Oxybenzone is the the viability of the reefs. most common photoallergen among all the UV Outside the United States oxybenzone has been filters.1 A 10-year retrospective analysis found that replaced in many sunscreens by other UV filters. 70.2% of almost 24,000 patients patch-tested with UV These include broad-spectrum filters such as bemo- filters between 2001 and 2010 had positive reactions trizinol and bisoctrizole, which are not currently to oxybenzone.2 In 2014, oxybenzone was largely available in the United States, and ecamsule, which is responsible for the naming of available in the United States benzophenones as contact only in products approved CAPSULE SUMMARY allergen of the year by the though the New Drug American Contact Dermatitis Application process. In 2015 d In addition to application of sunscreen, Society.3 Potential endocrine the FDA announced that proper photoprotection consists of effects of oxybenzone ecamsule, bemotrizinol, bi- seeking shade, wearing photoprotective were identified in several soctrizole, and 5 other sun- clothing and hat, and using sunglasses. in vitro studies4-6 and an screen ingredients that had in vivo study showed dose- d Ultraviolet filters have been well been awaiting approval in dependent estrogenic activ- established to be effective against the the United States through ity in 21-day-old rats adverse effects of ultraviolet radiation. the Time and Extent fed doses of oxybenzone d With increased understanding of the Application process were 7 ($1500 mg/kg/d). It should effect of visible light and infrared not generally recognized as be noted that the doses of radiation, studies on antioxidants and safe and effective, despite oxybenzone used in the an- oral and subcutaneous topical forms of approval by regulatory imal study were very high photoprotection are ongoing. agencies in many parts of and the estrogenic potency the world.20 detected was 1 million-fold less than the estradiol control.8,9 Short-term studies Antioxidants that looked at topical application of UV filters Traditional sunscreens provide effective protec- including oxybenzone in human beings found that tion against erythema but not similarly effective there were no significant UV filtererelated alter- protection against the generation of reactive oxygen ations on the endocrinologic effects on either repro- species (ROS) in the skin after exposure to UVR, ductive hormones10 or thyroid function.11 especially UVA.21 Therefore, antioxidants are incor- Mathematic modeling indicated that it would take porated in many sunscreen products because of their 277 years using a sunscreen containing 6% oxy- ability to scavenge and reduce levels of ROS, benzone used at 2 mg/cm2 (the dose recommended the primary mediator of oxidative damage to the for sun-protection factor [SPF] testing by the FDA) skin.22-24 Compared with sunscreen alone, the addi- or 1 mg/cm2 (reported real-life use) to achieve the tion of antioxidants has been shown to suppress ROS systemic levels of oxybenzone achieved in the formation by an additional 1.7-fold for SPF 4, and study in rats.12 Oxybenzone has been in use in the 2.4-fold for SPF 15 and 50 formulas, respectively.25 United States since at least the early 1970s with no Sunscreen with added antioxidant has been shown clinical report of estrogenic side effects. Thus, all to be more efficient than sunscreen alone in sup- current data indicate that oxybenzone is safe. pressing other changes in the skin known to be Nonetheless, in the European Union the label of induced to exposure to UVR such as development of a sunscreen containing oxybenzone must include pigmentation, depletion of Langerhans cells, and a cautionary statement (‘‘contains benzophenone- induction of matrix metalloproteinase (MMP)-9.22-24 3’’) if the concentration is over 0.5%.13 These and other data indicate that addition of Oxybenzone has also emerged as a potential antioxidants to sunscreens represents a potentially hazardous environmental contaminant. Water sam- effective strategy to minimize UV damage. The pling studies have shown that it is not fully antioxidants that have been studied include vitamins eliminated during waste water treatment,14,15 and A (retinol), C (ascorbic acid), and E (a-tocopherol), oxybenzone and its metabolites have been and (e)-epigallocatechin-3-gallate, a polyphenol detected in fish, with antiandrogenic and anties- component of green tea. Antioxidants are inherently trogenic effects.16,17 A genotoxic effect of oxy- unstable compounds, however, so are difficult to benzone on coral was recently reported in a formulate in an acceptable, stable, and biologically laboratory study,18 supporting earlier evidence of active composition for sunscreen products. A 2011 bleaching effects on coral in the Atlantic, Pacific, analysis of 12 commercially available US sunscreens JAM ACAD DERMATOL Lim, Arellano-Mendoza, and Stengel S93 VOLUME 76, NUMBER 3 with added antioxidants listed in their labels indi- studies reported low serum 25(OH)D levels associ- cated that 10 had no antioxidant power at all ated with sunscreen application.37-39 However, a (measured as the compound’s capacity to remove a 2009 review of the available evidence concluded certain number of free radicals in certain time that although sunscreens can significantly reduce the 26 intervals) and the other 2 had only low power. production of UVB-induced previtamin D3 when applied under strictly controlled conditions, in real Nanoparticles life, normal use does not generally result in vitamin- The safety of sunscreens containing inorganic UV D deficiency.40 This is mainly because of inadequate filters of titanium dioxide and zinc oxide nano- application of sunscreen to the skin; most people do particles (single particles of diameter \100 nm) not apply it at the dose recommended for SPF testing came into question after both were shown to induce (2 mg/cm2), resulting in an in-use SPF that is a few- formation of free radicals in vitro on exposure to fold lower than the SPF on the label. UVR, which could potentially damage viable cells Supporting evidence that the use of sunscreens in in vivo.27 However, it should be noted that when real-life settings does not decrease serum 25(OH)D used in sunscreen, nanoparticles are coated with levels came from an analysis of data from 5920 materials to almost completely block emission of adults in the 2003 to 2006 National Health and ROS into the skin and to reduce cytotoxicity by Nutrition Examination Survey, which concluded that preventing adherence of the nanoparticles to cells. A frequent sunscreen use has no effect.41 In contrast, number of recent reviews concluded there is no seeking out shade and wearing long sleeves were evidence of any related adverse consequences for significantly associated with lower 25(OH)D levels human health.27-30 Concerns that nanoparticles and vitamin-D deficiency [25(OH)D #20 ng/mL], could penetrate the skin were investigated ande especially in white individuals, but wearing a hat based on current evidenceenanoparticles appear to and using sunscreen use were not (Fig 1). These remain on the surface of the intact human skin.27 associations were much weaker in Hispanic and Although they can lodge in hair follicles, they appear black adults. The authors suggested that the lack of confined to the stratum corneum after topical appli- association between frequent sunscreen use and cation and do not penetrate the dermoepidermal lower serum 25(OH)D levels might be a result of junction. Although there is no evidence of percuta- application of sunscreen only before intentional neous absorption or penetration of intact skin, there prolonged sun exposure, which was reported in 2 are insufficient data on inflamed skin where the studies in which use of sunscreens was associated epidermal barrier function has been altered, so care with prolonged sun exposure42 and sunburns.43 should be taken in applying nanoparticles in sun- Patients who practice rigorous photoprotection, screen in the individuals with altered skin barrier such as those with lupus erythematosus,44 erythro- function. Other methods of photoprotection (eg, poietic protoporphyria (EPP),45 or photosensi- staying in the shade, wearing photoprotective tivity,46 have low 25(OH)D levels (#20 ng/mL). clothing) is more appropriate for individuals in Similarly, in a recent investigation, 21 patients with whom the skin barrier has been severely compro- xeroderma pigmentosum were found to have signif- mised, eg, in those with very severe eczema. icantly suppressed levels of 25(OH)D (median 19 nmol/L).47 VITAMIN D The American Academy of Dermatology cautions It has been suggested that blocking UVB with against obtaining vitamin D from unprotected expo- sunscreen could lead to vitamin-D deficiency by sure to UVR,48 and supports recommendations from preventing the conversion of 7-dehydrocholesterol the Institute of Medicine for vitamin-D supplemen- (also known as provitamin D) in the skin to tation in individuals at risk for vitamin-D insuffi- previtamin D3, the precursor of the biologically ciency, which include adults aged 71 years or older; active vitamin D. Vitamin-D insufficiency/deficiency, individuals with limited sun exposure, with dark skin defined variously as total serum 25-hydroxyvitamin or fat malabsorption, and who are obese, because D [25(OH)D] of 20 ng/mL or less (#50 nmol/L)31 or vitamin D is a fat-soluble vitamin; and breast-fed 30 ng/mL or less (#75 nmol/L),32 is associated with infants, because human milk is a poor source of increased risk for fractures, falls, cardiovascular dis- vitamin D. According to recent US Preventive ease, cancer, diabetes, depression, cognitive decline, Services Task Force guidelines, although vitamin-D and death.33,34 Deficiency in vitamin D can arise testing is widely available, current evidence is from insufficient production in the skin from UVB insufficient to assess the balance of benefits and exposure and inadequate dietary intake, but may harms of screening for vitamin-D deficiency in also be a result of genetic predisposition.35,36 Several asymptomatic adults.49 S94 Lim, Arellano-Mendoza, and Stengel JAM ACAD DERMATOL MARCH 2017

leucotomos extract appear to be antioxidative and antiinflammatory; it has a low SPF (3-8).

Nicotinamide Nicotinamide is an active amide form of vitamin B3 (niacin; nicotinic acid) widely available as an oral dietary supplement. It is a precursor of nicotinamide adenine dinucleotide, an essential cofactor for pro- duction of adenosine triphosphate, which is essential for skin immune response and DNA repair. Unlike niacin, oral nicotinamide does not have vasodilatory effects and is not associated with a cutaneous Fig 1. Odds ratio of vitamin-D deficiency comparing flushing reaction. Nicotinamide has been shown to frequent with rare users according to sun-protective behav- prevent UVR-induced intracellular depletion of iors among US white individuals. SPF,Sun-protectionfactor. adenosine triphosphate,57 boosting cellular energy Ó Springer Science1Business Media B.V. 2011. With and enhancing DNA repair58,59 and preventing 41 permission of Springer. immunosuppression.60 In 2 phase II trials, subjects with sun-damaged skin who took 500 mg of oral ORAL AND SUBCUTANEOUS nicotinamide once or twice daily had, respectively, PHOTOPROTECTION 29% and 35% fewer actinic keratoses at 4 months There is growing interest in the potential for oral compared with patients on placebo.61 In a recently and subcutaneous agents to provide additional pro- reported phase III, double-blind, randomized tection against exposure to UVR and to further controlled trial, Oral Nicotinamide to Reduce reduce damage that ordinarily would lead to photo- Actinic Cancer, patients with a history of 2 or more aging and skin cancer. These agents are different nonmelanoma skin cancers who were given nico- from sunscreens in their mechanism of action, in the tinamide 500 mg twice daily had 23% lower rates of different end points important in measuring efficacy, new nonmelanoma skin cancers and 11% fewer and in the benefits of their use. Several orally and actinic keratoses than the placebo group after subcutaneously administered agents have been 12 months (Fig 2).62 This broad chemopreventive shown to have the potential to reduce the severity effect persisted with continuous treatment, but not of a sunburn, decrease photosensitivity, and prevent after discontinuation of nicotinamide. There were no photodamage; however, larger studies need to be differences in side effects between the treatment and done to confirm efficacy and safety. Several of these the control groups. agents are in late stages of clinical development. Afamelanotide Polypodium leucotomos extract Afamelanotide is a structural analog of a-melano- Polypodium leucotomos is a fern plant (botani- cyte-stimulating hormone that was shown to be cally known as Phlebodium aureum, Polypodium beneficial as an adjunctive photoprotective agent in aureum,orPolypodium leucotomos) that is native to patients with EPP and solar urticaria. As an agonist of Central and South America, where it is used in the melanocortin-1 receptor, afamelanotide pro- traditional medicine. Extract of the plant is commer- motes synthesis of melanin (eumelanin), which is cially available in many parts of the world as over- photoprotective, and acts as an antioxidant. In the-counter oral and topical formulations.50 Studies clinical trials, it was administered as a controlled- with the oral formulation have shown it to be release, subcutaneous implant that released the drug photoprotective against UVB- and psoralen plus over approximately 2 weeks; melanin concentration UVAeinduced toxicity,51,52 development of poly- was increased after 2 days, with the effect lasting up morphous light eruption,53-55 and possibly also solar to 2 months.63 After undergoing phase II and III urticaria.53,54 Polypodium leucotomos extract in- clinical trials in Europe and the United States,64-66 creases the UV dose required for immediate pigment afamelanotide, administered as 16 mg subcutane- darkening, minimal erythemal dose, and minimal ously every 60 days, received regulatory approval in phototoxic dose.51 A recently concluded short-term Europe for prevention of phototoxicity in adult study of oral Polypodium leucotomos extract admin- patients with EPP. In 2 randomized, double-blind, istered at 240 mg twice daily for 60 days in healthy placebo-controlled phase III studies, in 74 European individuals resulted in suppression of UVB-induced patients with EPP and in 94 US patients with EPP who erythema.56 The primary activities of Polypodium each received 5 or 3 subcutaneous implants, JAM ACAD DERMATOL Lim, Arellano-Mendoza, and Stengel S95 VOLUME 76, NUMBER 3

UVA. However, it is now known that chronic exposure to UVR, particularly UVA, and infrared (760-4000 nm) spectra, particularly those in the near infrared range (infrared A; 760-1400 nm), can result in photoaging changes. In addition, exposure to visible light (400-760 nm) results in pigmentary alterations lasting a few weeks in melanocompetent individuals. Consideration should therefore be given to photoprotection against visible light and infrared A.

Delayed photodamage Until recently, generation of cyclobutane pyrim- idine dimers (CPDs) was believed to only occur within picoseconds after irradiation with UVA or UVB. However, a 2012 study suggested that there Fig 2. Change from baseline to month 12 in number of actinic keratoses, adjusted for center: 11% lower in the might be 2 pathways for CPD generation in melano- nicotinamide group than in the placebo group at 3 months cytes when it revealed that CPDs could be readily (P = .01), 14% lower at 6 months (P \.001), 20% lower at detected in the skin of both albino and black mice 9 months (P\.001), and 13% lower at 12 months (P = .001). irradiated with UVB (280-320 nm), but not with UVA Copyright Ó 2015 Massachusetts Medical Society. Reprinted (320-400 nm).69 CPDs and 6-4 photoproducts were with permission from Massachusetts Medical Society.62 comparable in albino and black animals after UVB irradiation, but after UVA irradiation only thymine- respectively, every 60 days, those who received thymine-CPD lesions were detected, at lower levels afamelanotide experienced significant improve- compared with UVB irradiation, and no 6-4 photo- ments in duration of pain-free time under direct products were found. A more recent study showed sun exposure compared with placebo.66 Quality of that CPD production continues for several hours in life was also improved in both treatment groups, and melanin-containing murine melanocytes after UVA adverse effects were mostly mild (consisting of irradiation, whereas in melanocytes from albino headache, nausea, nasopharyngitis, and back mice, peak CPD induction is seen immediately after pain). In the longer European study, phototoxic UVA exposure.70 The CPDs produced later after reactions were significantly less severe, with shorter irradiation were termed ‘‘dark CPDs.’’ In mice with recovery time in patients on afamelanotide. melanocytes containing red-yellow pheomelanin, Afamelanotide has also been investigated as treat- rates of formation of both initial and dark CPDs ment of solar urticaria in a small study of 5 patients; it were twice those in black mice, suggesting that resulted in increased synthesis of melanin and an pheomelanin is both a poorer protection against increase in tolerance to artificial light exposure.67 It normal CPD formation and a more potent generator should be noted that a phase III trial with afamelano- of dark CPDs. This is consistent with the observation tide in polymorphous light eruption was started in that individuals with Fitzpatrick skin type I or II, who 2007 and completed in 2010 (NCT00472901), and a have high ratios of pheomelanin to eumelanin, are at phase II trial against actinic keratosis in organ trans- higher risk for skin cancer. The proposed mechanism plant recipients was started in 2009 with unreported for the formation of dark CPD is that UVR induces study conclusion (NCT00829192). The results of ROS and nitrogen species that excite electrons in these 2 trials have not been published to date. melanin to a high-energy triplet state moiety that transfers energy to DNA hours after UV exposure. Topical endonuclease This indicates that melanin may be carcinogenic and Topical application of bacteriophage T4 endonu- protective against cancer and underlines the impor- clease 5 in a liposomal lotion in patients with tance of the use of sunscreen or physical protective xeroderma pigmentosum was shown to decrease agents. Systemic or topical antioxidants may be photocarcinogenesis process.68 Studies are still beneficial in preventing dark CPD formation.70 ongoing. Visible light PHOTODAMAGE Visible light (400-760 nm) accounts for 40% to 45% For a long time, the focus of photoprotection of the electromagnetic radiation that reaches the was prevention of the immediate effects of UVB/ earth’s surface. Few investigators have reported its S96 Lim, Arellano-Mendoza, and Stengel JAM ACAD DERMATOL MARCH 2017 biological effects on human skin, but it has been in skin temperature.80 Infrared is now recognized as reported to cause changes in pigmentation and having biological effects on human skin.81,82 Infrared erythema,71-75 thermal damage and free radical pro- A irradiation include the activation of mitochondrial duction, and production of ROS.24 In 2010, investi- ROS via up-regulation of MMP-1, -3, and -13, without gators using a light source emitting 98.3% visible light concomitant up-regulation of tissue inhibitor of on skin types IV to VI showed that pigmentation metalloproteinase-1, resulting in collagen degrada- induced by visible light was darker than that induced tion.83 Repeated exposure to infrared A is associated by long-wave UVA (UVA1, 340-400 nm, 20 J/cm2) and with the appearance of coarse wrinkling, a charac- at higher doses, surrounded by erythema that teristic of photoaging, in the skin of mice83 and disappeared within 2 hours of exposure.73 In human beings.84 In mouse skin, wrinkle formation contrast to UVA1, pigmentation induced by visible was greater with infrared A plus UVR than with either light was sustained over the 2-week period of the infrared A or UVR alone, indicating that infrared A study and did not fade away even at lower doses. No causes photoaging through different mechanisms. pigmentation could be induced in skin type II, Infrared A has also been shown to reduce type 1 suggesting that the response to visible light and collagen expression by inhibiting the production of UVA is dependent on skin type. This suggests that procollagen-1-stimulating transforming growth fac- visible light plays a role in conditions aggravated by tor-b1, -b2, and -b3,85 and to induce angiogenesis in sun exposure such as melasma and postinflamma- human skin through increased expression of tory hyperpigmentation, which is especially com- vascular endothelial growth factor,86 and it has mon in darker-skinned individuals (skin phototypes been shown to increase numbers of mast cells. III-VI). A subsequent study showed that pigmenta- Infrared A has been shown to confer resistance to tion was induced in individuals with skin types III UV-induced apoptosis via reduction of DNA damage and IV with 415-nm, but not 630-nm radiation; the and up-regulation of antiapoptotic proteins.87 Some pigmentation lasted 3 months.76 studies of the effects of infrared A have been Currently available organic (chemical) UV filters criticized for using artificial infrared A sources of are not sufficient to protect the skin from the effect of higher intensity than real-life daily exposure with the visible light; only optically opaque filters such as result that skin damage caused by infrared A at real- nonmicronized form of zinc oxide and titanium world intensities has not been conclusively dioxide, and iron oxide, are able to block visible demonstrated.88 light.77 These compounds scatter and reflect visible Currently there are no organic (ie, chemical) or light. Recent studies demonstrated that addition of inorganic (ie, physical) filters specifically directed these compounds to sunscreens provide greater against infrared A; claims that sunscreens protect protection in terms of decrease in Melasma Area against infrared Aeinduced skin damage are not and Severity Index score.78,79 However these com- regulated. Sunscreens with infrared A-reflecting pounds are matt white or red in color, water- inorganic filters such as titanium dioxide would be insoluble, and leave a white or tinted coating on effective, but it is unlikely that they would be widely the skin, which is unacceptable to many patients. used (see Young et al). The demonstration that ROS Topically applied antioxidants may also be beneficial plays a crucial role in the pathogenesis of infrared against the effects of visible light, as suggested by the Aeinduced skin damage has led to the testing of findings that use of a photostable UVA/UVB sun- antioxidant agents. Topical application of b-carotene screen containing an antioxidant combination signif- (2 mg/cm2) was reported to protect human skin icantly reduced the production of ROS, cytokines, exposed to infrared radiation.89 In a proof of prin- and expression of MMPs in vitro, and decreased ciple study, topical application of a commercially oxidative stress in human skin after visible light available antioxidant mixture containing vitamin C, irradiation.24 vitamin E, ubiquinone (coenzyme Q10), and a grape (Vitis vinifera) seed extract effectively prevented Infrared radiation infrared Aeinduced MMP-1 messenger RNA expres- More than 50% of the solar radiation/energy that sion in vivo in human skin.84 The same mixture reaches earth is infrared radiation (infrared, 760 nm-1 added to SPF 30 sunscreen applied by 30 healthy mm). The most widely studied wavelength band is volunteers significantly reduced MMP-1 messenger near infrared (infrared A, 760-1400 nm), which RNA expression compared with SPF 30 sunscreen represents about one third of total solar energy and alone.90 Grape seed extract includes several flavo- can penetrate human skin, directly affecting cells nols (catechin and epicatechin), procyanidins, and located in the epidermis, dermis, and subcutis. phenolic acids, all of which have been reported to Exposure to infrared produces a perceptible increase act as antioxidants.91 Grape seed extract is marketed JAM ACAD DERMATOL Lim, Arellano-Mendoza, and Stengel S97 VOLUME 76, NUMBER 3

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